Arylaminoalkyl hydrazines and aralkylaminoalkyl hydrazines



United States Patent 0 3,197,474; ARYLAh ENUALKYL HYDRAZLQES ANDARALKYLAMHNGALKYL HYDRAZENES Jiohn lhi. his lylilwnulree, Wis.,assignor, by mesne assignments, to Colgate-Palmolive Company, acorporation of Deiau'are No Drawing. Filed Feb. 3, 19nd, Ser. No. 6,33918 Claims. (62. ass-ass This invention relates to hydrazine derivatives.More particularly, this invention is concerned with arylarninoalkyl andaralkylaminoalkyl hydrazines and the use of these compounds aspsychotherapeutic' agents. The invention is also concerned with novelpharmaceutical com positions containing an arylaminoalkyl oraralkylaminoalkyl hydrazine.

This application is a continuation-in-part of my copending application,Serial No. 828,020, filed July 20, 1959, now abandoned, which in turnwas a continuationin-part of our application, Serial No. 679,520, filedAugust 21, 1957, now abandoned, my application Serial No. 726,356, filedApril 4, 1958, now abandoned, and my application Serial No. 765,928,filed October 8, 1958, now abandoned.

It has now been discovered according to the present invention thatarylaminoalkyl and aralkylarninoalkyl hydrazines of the formula arepotent monoamine oxidase inhibitors and central nervous systemstimulants useful for psychotherapeutic treatment of depressed mentalstates, wherein Ar is an aryl group such as phenyl, a substituted phenylgroup such as lower alkyl phenyl groups like methylphenyl, halophenylgroups like chlorophenyl, lower alkoxy-phenyl groups like methoxyphenyl,lower alkylenedioxyphenyl groups like methylenedioxyphenyl, pyridyl,imidazolyl, thienyl and furyl, R is hydrogen, an alkyl group andparticularly a lower alkyl such as methyl, ethyl, propyl, butyl and thelike, an alkenyl group such as allyl or the 1-(2-butenyl) group, anaralkyl group and particularly phenyl-lower alkyl groups such as benzyland phenethyl, an aryl group and particularly the phenyl group, acycloalkyl group and particularly the cyclopentyl or cyclohexyl group,and heterocylic-lower alkyl groups such as 3 pyridylmethyl, thenyl,Z-I'urfurylrnethyl, Z-furylrnethyl, and 2-imidazoylmethyl, R is hydrogenor a lower alkyl such as methyl,

ethyl, propyl or isopropyl, and R and R are the same or different groupsof the group consisting of hydrogen alkyl group and particularly thelower alkyl groups including methyl, ethyl, propyl, butyl, pentyl andhenyl, acyl groups such as actyl, propionyl, butyryl, benzoyl, palmitoyland phenylacetyl, hydroxy-alkyl groups such as hydroxyrnethyl,Z-hydroxyethyl and 3-hydroxypropyl, alkenyl groups and particularlylower alkenyl groups such as the allyl group and the l-(2-butenyl)groups, aryl groups and particularly the phenyl group including nuclearsubstituted phenyl groups such as hydroxyphenyl, methoxyphenyl,chlorophenyl, acet-oxyphenyl and the like, aralkyl groups andparticularly phenyl-lower alkyl groups such as the benzyl, phenethyl,phenylpropyl and chlorophenylpropyl groups, cycloalkyl groups such asthe cyclopentyl and cyclohexyl groups, alkynyl groups such as propynylor butynyl, and groups in which represents a cyclic secondary aminogroup such as the morpholino, pyrrolidino, piperidino,1,2,3,4-tetrahydroisoquinolino, 1,2,3,4-tetrahydroquinolino,isoindolino, 4- ethyl-l-piperazino, hydroxypiperidino, indolino,theophyllino and phenothiazino groups, Y is a or einical bond or astraight or branched alkylene group of not more than five carbons, B isa straight or branched lower alkylene group, R is hydrogen or a loweralkyl group and the group B-OH is advisably not more than five carbons.

Although I do not Wish to be restricted to a theory, it is consideredthat these compounds pass through the blood-brain barrier and, becauseof their monoamine oxidase inhibitory property, retard or prevent themetabolic destruction of neurohumoral agents such as serotonin andnorepinephrine. Serotonin and norepinephrine are present in the brainand apparently serve as chemical transmitters in, or stimulants of, thecentral nervous systern. A deficiency of available serotonin ornorepinephrine in the brain, such as can be caused by metabolism ordegradation of these agents by monoamine oxidase, may result inparasympathetic predominance present in depressed mental states. Bypreventing or retarding destruction of serotonin and norepinephrinethrough the use of these hydrazines the levels of these neurohumoralagents present in the body are maintained higher for longer periods oftime so that sympathetic characteristics such as increased awareness andmotility result. These hydrazines also stimulate the heart musle and arethus useful for the treatment of a person in a state of shock. Thecompounds also form salts with penicillin and thus can be used toisolate and purify this antibiotic. These compounds are advisablyemployed in the described uses in the form of a nontoxic acid additionsalt such as the hydrochloride, hydrobromide, fumarate or sulfate.

Some of the novel arylaminoalkyl and aralkylaminoalkyl hydrazines may beconveniently prepared by reacting an arylarninoalkyl oraralkylaminoalkyl halide with hydrazine or a monosubstituted hydrazine.This process may be represented as follows:

A1-Y-NB-GHX RgNH-NE;

Ar-YN-BCH-NNH2 R1 R5 R2 wherein Ar, R R Y, B and R have the significancepreviously assigned and X is a reactive halogen such as bromine,chlorine, or iodine.

Some of the arylaminoalkyl and aralkylaminoalkyl halides Which may beused in this process are N-phenylamino-ethyl chloride,Nphenyl-N-methylaminoethyl chloride, N-phenyl-N-alkyaminoisoproylbromide, N-2-pyridyl-N-rnethylaminoethyl chloride,N-3-pyridyl-l-lmetl1ylaminoisopropyl chloride,N-Z-thienyl-N-isopropylarninosec-butyl chloride, N 2 furyl N sec'butyiaminoethyl chloride, N-Z-imidazolyl-N-isopropylaminoethyl bromide,N-benzyl-N- methylarninoethyl chloride, N-benzyl-N- allylaminoisopropylbromide, N 2 pyridylmethyl i' L methylaminoethyl chloride, N-3-pyridylmethyl-N-methylaminoethyl chloride, N 4 pyridylmethyl Nmethylaminoethyl chloride, N-2-thenyl-N isopropylamino sec- Y butylchloride, N-Z-furfurylmethyl N methylaminoisopropyl bromide,N-Z-imidazolylmethyl-N-sec-butylaminoethyl chloride,phenylpropylaminoethyl chloride and N- phenylethyl-N-methyl-aminomethylchloride.

In addition to hydrazine hydrate, monosubstituted hydrazines such asrnethylhydrazine, ethylhydrazine, isopropylhydrazine and butylhydrazinemay be used in the process.

The reaction is efiected by adding the arylaminoalkyl oraralkylaminoalkyl halide to a solution of a large excess, such as about200%, of the hydrazine reactant in a solvent such as methanol, ethanol,butanol or dioxane. In creased temperatures such as up to refluxtemperature are generally employed to increase the reaction rate. Bydistilling oh the solvent, extracting the residue with a solvent such asether and then fractionally distilling the extract, the desired reactionproduct may be recovered.

Some .of the arylaminoalkyl and aralkylaminoalkyl hydrazines which maybe produced in thisway are N- phenylaminoethyl hydrazine,N-phenyl-N-methylaminoethyl hydrazine, N phenyl N allylaminoisopropylhydrazine, N-Z-pyridyl-N-methylaminoethyl hydrazine, N- 3-pyridyl-N-methylaminoisopropyl hydrazine, N 2 thienyl-N-isopropylamino-sec-butylhydrazine, N-Z-furyl-N- sec-butyl-aminoethyl hydrazine, N-Z imidazolyl Nisopropylaminoethyl hydrazine, N-benzyl N methylaminoethyl hydrazine,N-o-chloro-benzyl N methylaminoisopropyl hydrazine,N-(l-phenyl-Z-propyl)-aminoethyl hydrazine, N- l-phenyl-Z-propyl-aminoisopropyl hydrazine, N phenethylaminoisopropyl hydrazine, Nbenzylaminoethyl hydrazine, N-Z-thenyl-N-isopropylamino-sec-butylhydrazine and N-Z-furfurylmethyl N methylaminoisopropyl hydrazine. 7

Those compounds in which R and R are both substituents other thanhydrogen, as well as compounds in which one or both of R and R arehydrogen, may be conveniently produced by reacting an arylaminoalkyl oraralkylaminoalkyl ketone or aldehyde with hydrazine or a substitutedhydrazine to produce an intermediate arylaminoalkylidenyl oraralkyl-aminoalkylidenyl hydrazine, or hydrazone, which is then reducedto the corresponding hydrazine. This process may be represented asfollows:

wherein Ar, Y, R R and R have the significance previously assigned, B isa lower alkylene group and R is hydrogen or a lower alkyl group.

Representatives of the arylaminoalkyl and aralkylaminoalkyl ketones andaldehydes which may be used in this process are N-phenyl-N-methylaminoacetaldehyde, 2-(N-o-chlorophenyl-N ethylamino) propionaldehyde,alpha-(N-3 pyridyl-N-methyl amino) 2 propanone, 2- thienyl-methylaminopropionaldehyde, N-phenyl-N-ethylaminopropyl methyl ketone, Z-furylaminoacetaldehyde, N-benzyl-N-methylamino acetaldehyde,2-(N-ochlorobenzyl-N-ethylamino) propionaldehyde, alpha (N 3-pyridylmethyl-N-methylamino)-2-propanone, alpha '(N-4-pyridylmethyl-N-methylamino)-2-butanone, 2 thienylmethylarninopropionaldehyde, N phenethyl N ethylaminopropyl methyl ketone, and2-furylmethylamino acetaldehyde.

Representatives of the hydrazines which may be used in the process arehydrazine, acyl hydrazines such as acetyl hydrazine, propionylhydrazine, benzoyl hydrazine, phenylacetyl hydrazine, isonicotinylhydrazine, monosubstituted hydrazines such as methylhydrazine,ethylhydrazine and benzylhydrazine, phenethylhydrazine andN,N-disubstituted hydrazines such as N,N-dimethylhydrazine,N,N-diethylhydrazine, N,N-dibenzylhydrazine, N,N- diphenethylhydrazine,N-ethyl-N-benzyl hydrazine, N- amino 1,2,3,4-tetrahydroisoquinoline,N-amino-pyrroli dine, N-amino-tetrahydroisoindoline,N-amino-It-hydroxysnee /347a piperidine and N-amino-morpholine. Theproduction of some or these hydrazines is shown in my copendingapplication Serial No. 681,189, filed August 30, 1957.

Reaction between the ketone or aldehyde and the hydrazine isconveniently eitected by contacting the reactants in the presence ofwater or a lower alcohol. The reaction proceeds at room temperaturealthough slightly elevated temperatures may be employed to increase therate of reaction. Recovery of the intermediate alkylidenyl hysuch asether. The product is readily isolated by distillation under reducedpressure.

The intermediate hydrazone may be reduced to the corresponding hydrazineby use of a suitable reducing agent. Lithium aluminum hydride is thepreferred reducing agent although catalytic hydrogenation also may beemployed. With lithium aluminum hydride, the reduction may beconveniently eifected by intimately combining the reactants in an inertorganic solvent such as anhydrous ether, dioxane, or tetrahydrofuran.Elevated temperatures such as the reflux temperature enhance thereaction. At reflux temperature from 1 to 8 hours is usually sufiicientto substantially complete the reaction. After the reaction isterminated, water may be added to the mixture to decompose excesslithium aluminum hydride. To recover the product the organic phase isseparated and the aqueous residue extracted with the same solvent. Theorganic phase and extracts then may be combined, dried, and the productdistilled.

Some of the hydrazines produced in this way besides those namedpreviously having two carbons between the hydrazine and amine moietiesare 1- (N-2-pyridyl-N-methylaminoethyl) 2-N',N-dimethylhydrazine,

N- (phenylaminoethyl) -N-morpholino amine,

1-(N-Z-thienyl-N-methyl-aminoethyl)-2-N-methyl hydrazine,

N- (phenylaminoethyl) -N,N-di-hydroxymethyl hydrazme,

1- N-Z-pyridylmethyl-N-methylaminoethyl) -2-N',N- dimethylhydrazine, i

1- N-Z-thienylmethyl-N-methyl-aminoethyl) -2N'-methyl hydrazine,

N- (benzylaminoethyl) -N-morpholino amine,

N-(N-phenylisopropyl-N-ethyl aminoethyl)-N',N'-dibenzyl hydrazine,

N-(Z-thenylaminopropyl) N',N'-dipropyl hydrazine,

N-(Z-pyridylethylaminoethyl)-N-pyrrolidino amine, and

N- (benzylaminoethyl) -N,N-di-hydroxyethyl hydrazine.

The hydrazines in which R and R are substituents other than hydrogen maybe converted to the compounds of Formula I in which R is an alkyl oraralkyl group by the process of reductivealkylation employing aformaldehyde-formic acid mixture or an alkyl or aralkyl acyl halide, orequivalent ester, to form an intermediate acyl hydrazine and reducingthe acyl group 'to an alkyl or alkylene group. This process may berepresented as follows:

wherein Ar, R Y, R and R have the significance previously assignedexcept that neither R nor R is hydrogen,

J A is a reactive halogen such as chlorine, bromine or iodine or a loweralkoxy group, and Z represents R and R is a lower alkyl, aryl (phenyl)or aralkyl (phenyllower alkyl) group. R

In addition to the formaldehyde-formic acid mixture which can be used tointroduce a methyl group for R in Formula I, one may also use an alkylformate to introduce the formyl group which then may be reduced as byplatinum and hydrogen, or lithium aluminum hydride, to the methyl group.

Other esters or acyl halides may also be used to lntroduce theintermediate acyl group. Some such reactants 4 which may be used areacetylchloride, propionylbromide, benzoylchloride, phenylacetylchloride,ethyl phenylacetate, phenylpropionylchloride, methylacetate and thelite.

The acylation reaction is effected by contacting the reactants in aninert solvent such as ether or tetrahyorofuran and refluxing themixture. Reduction of the intermediate acyl hydrazine is readilyeffected without isolation of the acyl compound by use of lithiumaluminum hydride or catalytic hydrogenation. Some of the com poundsproduced in this way are N-(phenylaminoethyl)- N-methyl-N-,N-dimethy1hydrazine, N-(benzylaminoethyl) N methyl-N-N-dimethyl hydrazine,N-(phenethylaminopropyl)-N-phenethyl-N-morpholino amine and N (Nbenzyl-N-cthyiaminoethyl)-N-ethyl-N,N-di-hydroxyethyl hydrazine.

Acid addition salts of the novel hydrazines are produced by contactingthe hydrazine with a mineral or organic acid. Acids such ashydrochloric, formic, maleic, fumaric and citric may be used to formsalts of the hydrazines.

The hydrazines may be administered to animals and humans as purecompounds. It is advisable, however, to first combine one or more of thenovel compounds with a suitable pharmaceutical carrier to attain a moresatisfactory size to dosage relationship.

Pharmaceutical carriers which are liquid or solid may be used. Thepreferred liquid carrier is water. Flavoring materials may be includedin the solutions as desired.

Solid pharmaceutical carriers such as starch, sugar, talc and the likemay be used to form powders. The powders may be used as such for directadministration to a patient or, instead, the powders may be added tosuitable foods and liquids, including Water, to facilitateadministration.

The powders also may be used to make tablets, or to fill gelatincapsules. Suitable lubricants like magnesium stearate, binders such asgelatin, and disintegrating agents like sodium carbonate in combinationwith citric acid may be used to form the tablets.

Unit dosage forms such as tablets and capsules may contain any suitablepredetermined amount of one or more or" the hydrazines, advisably as anontoxic acid addition salt, and may be administered one or more at atime at regular intervals. Such unit dosage forms, however, shouldgenerally contain a concentration of 0.1% to by weight of one or more ofthe active hydrazines.

A typical tablet may have the composition:

Powders l, 2 and 3 are siugged, then granulated, mixed with 4 and 5, andtableted.

Capsules may be prepared by filling No. 3 hard gelatin capsules with thefollowing ingredients, thoroughly mixed:

Mg. (1) N 3 pyridylmethyl N-methylamino-2-propyl hydrazine 5 d (2)Lactose, U.S.P. 200 (3) Starch, U.S.P. l6 (4) Talc, U.S.P. 8

The oral route is preferred for administering the active hydra/zines.

According to a further embodiment of this invention one or more of thehydrazines is administered simultaneously with, or concomitantly to, theadministration of either tryptophan and/ or phenylalanine to an animalor uman. Tryptophan passes the blood-brain barrier and is converted inthe brain to serotonin. Serotonin is not administered directly since itcannot pass the blood-brain barrier. Similarly, phenylalanine passes theblood-brain barrier and is converted in the brain to norepinephrine.Norepinephrine itself will not pass the blood-brain barrier so it is notgiven directly. By the administration of an active hydrazinesimultaneously with, or concomitantly to, either tryptophan orphenylalanine the monoamine oxidase inhibitory property of the hydrazineretards or prevents the degradation of serotonin and/or norepincphrinewhich are produced in the brain from the said amino acids. The serotoninand norepinephrine levels are thus not only raised but are maintained atthe increased level by the described treatment.

Any suitable amounts of tryptophan and/or phenylalanine may beadministered since these materials are nontoxic. Duo or both of thesematerials is advisably combined with one or more of the activehydrazines into suitable pharmaceutical formulations.

The following examples illustrate the methods of making the compounds.

EXAMPLE 1 Z-(N-metlzyl-N-benzyZ-amino)ethyl hydrazine Olnn -C,H.,NHNH,

To 168 g. (2.85 mole) of hydrazine hydrate in 200 cc. of boilingmethanol was added 104.7 g. (0.475

EXAMPLE 2 N-3-pyridylmethyl-N-methylamino-Z-propyl hydrazine Thiscompound was prepared from N-3-pyridylmethyl- N-methylamino-Z-propylbromide and an excess of hydrazine as described in Example 1; B.P.120-l22 C. (0.3 mm.).

EXAMPLE 3 2- N -metlzyl dV-benzyl amino -ethylidenyl hydrazine 54.4grams (0.2 M) of N-methyl-N-benzylamino acetal was hydrolyzed by addingit slowly with cooling to 275 g. of concentrated hydrochloric acid. Themixture was refrigerated overnight and then taken to dryness in vacuo.50 cc. of water was added to the residue and then 20% NaOH added to pH7. The product was dissolved in cc. of methanol and added with stirringto 47 g. (0.8 M) of 85% hydrazine hydrate in 250 cc. of methanol. It waslet stand overnight at room temperature, part of the solvent distilledolf, and 400 cc. of water added. Itwas made strongly alkaline with KOH,extracted with a total of 400 cc. of etherand dried over anhydrous Kresidue fractionated through a 3" column. Yield 27.3 g. (77% B.P. 120C./1.0 mrn., N 1.5522.

Analysis.Calcd. for C H N N, 7.90%. Found: N, 7.97%. a

I EXAMPLE 4 2-(N-methyl-N-benzylamino)ethyl hydrazine In a 500 ml. flaskwas placed 5.3 g. (0.14 M) of LiAlH The ether was distilled off and the'in 200 ml. of dry ether. A solution of 25.5 g. (0.144 M) a Found:

EXAMPLE 5' v 2-(N-mzhyl-N-benzylamino)ethyl hydrazine dimaleate Asolution of 5.4 g. of the base in 30 ml. of ether was added to asolution of 8.1 g. of maleic acid in 75 ml. of ethanol. Yield 6.8 g.,MP. 124-125" C.

Analysis.-Calcd. for C H N G Maleic acid, 56.42%; N, 6.81%. Found:Maleic acid, 57.91%; N, 6.83%.

EXAMPLE 6 N -2 (N -0-chlor0benzyl-N '-methylamin10 ethyl hydrazine 34grams (0.125 M) of N-methyl N-o-chlorobenzyl amino acetal was added to65 cc. of concentrated hydro chloric acid at 510 C. The excess acid andwater were distilled ofi under vacuum with a 50 C. water bath. Theresidue was diluted to 125 cc. volume with water and neutralized to pH 7with 17 cc. of 10% sodium hydroxide. This solution was added to 36.7 g.(0.625 M) of 54.5% hydrazine at 5 C. and left standing overnight. Thesolution was saturated with sodium hydroxide with cooling, and the oilwas extracted with three 75 cc. portions of ether. The extracts weredried over K CO briefly and the solvent was distilled off through a 5"column. Residue weighed 25.15 g., 95.3%.

To 5.7 g. (0.15 M) of lithium aluminum hydride in 150 cc.tetrahydrofuran was added a solution of the hydrazone in 100 cc. oftetrahydrofuran in twenty minutes. The mixture was refluxed for threehours and the complex decomposed with 25 cc. of 40% KOH. The salts werefiltered off and washed with tetrahydrofuran. The extracts were driedover K CO the solvent distilled ofl through a5 column and the residuevacuum distilled; B.P. 8387 C. at 0.015 mm, wt. 7.45 g., N 1.5394.

Analysis.-Calcd. for c d-1 N 61: N, 6.55%. Found: N, 6.39%.

A PLE 7 N -2-(N -0-chl0r0benzyl-N methylamino) ethyl hydrazine dimaleazeTo 7 g. (0.06 'M) of maleic acid dissolved in 50 ccl ethanol was added asolution of 6.45 g. (0.03 M) of the base in 50 cc. of anhydrous ether.The solid was filtered off, washed with alcohol, dried and weighed, 6.75g. or 50.3% yield, M.P. l2l122 C.

Analysis.-Calcd. for C H N ClO N, 6.28%. Found: N, 6.33%.

Neutral equivalent:,111.46%. Found: 107.48%.

26.64%. Found: N, 15.42%;01, 26.47%.

..- EXAMPLE 8 J-(N-benhyl-N-methylaminoethylidenyl)-N',N-dim'ethylhydrazine ,acetaldehyde hydrochloride in 150 cc. of water wasadded 12.0 g. (0.20 mole) of N,N-dimethylhydrazine. The mixture wasstirred at room temperature for 16 hours, made strongly alkaline withsolid KOH and extracted with ether.

The ether solution was used in the subsequent of Example 9. V

. a V 7 EXAMPLE 91-(N-benzyl-N-mezhylaminoethyl)-N',N'-dimethylhydrazine An ethersolution of the ethylidene derivative from Example 8 was reduced with7.6 g. (0.20 mole) of lithium aluminum hydride in the usual manner, B.P.110-1 12 C. (0.50 mm.).

EXAMPLE '10 N-(I-phenyl-Z-propyl)-amin0ethyl chloride hydrochloride CHCH(CH NH c H,c1-Hc1 In a 500 cc. 3-neck round bottom flask equipped withmantle, stirrer, condenser, and gas inlet tube, was placed g. (0.45 M)of N-(l-phenyl-2-propyl)-aminoethanol dissolved in 180 cc. ofchloroform. Anhydrous hydrochloric acid was bubbled into the solutionuntil a pH of 2.0 was reached. Heating was begun and M9 g. (1.0 M) ofthionyl chloride was added dropwise. The solution turned black. It wasrefluxed two hours after the thionyl chloride addition. The chloroformwas removed in vacuo leaving 11 5 g. (0.45 M)'of a brown oily residue.

EXAMPLE 1 1 N (1 -phenyl-2 -pr0pyl -aminoethyl hydrazine CH CH CH NH--CH NHNH with cc. of ethyl ether. The ether extracts were dried overanhydrous potassium carbonate and concentrated on a steam bath. Theresidue, 52 g. (0.27 M), was distilled thru a 4" Vigreaux columnyielding 27.5 g. boiling at 121- 126 C. (0.4 mm.). The yield was 50%.

EXAMPLE l2 N'-(1-phenyl-2-pr0 pyl) -amin0ethyl hydrazine dihydrochloride27.5 g. (0.13 M) of N-('1-phenyl-2-propyl)-aminoethyl hydrazine wasdissolved in 300 cc. of ethyl ether. To this was slowly added, withmixing and cooling, 75 cc. of ethereal hydrochloric acid (4.18 N). Agummy precipitate was formed. It was cooled and the ether was thendecanted cautiously. The gummy precipitate was crystallized in a 1:3mixture of isopropyl alcohol and acetonitrile, filtered, washed, anddried in a desiccator; yield, 45 g., MP. (shrinks at 13 5" C.), 140-160C. The 45 g. was recrystallized in 200 cc. of hot ethanol yielding 20 g.of product. The percentage yield was 54%. MP. (shrinks at 0.), 203 C.;foams 210-212 C..

Analysis.Calcd. for C H N Cl N, 15.79%; Cl,

9 EXAMPLE 1s A solution of 47.6 g. (0.2 mole) of N-methyl-N-(4-fluoro)benzylamino ethyl chloride hydrochloride in 250 cc'. of ethanolwas added over a period of 2 hours to a stirred refluxing solution of70.4 g. (1.5 mole) of hydrazine hydrate 85% in 250 cc. of ethanol. After2 more hours of reflux most of the alcohol was removed by distillation.After addition of potassium hydroxide solution the mixture was extractedwith ether, dried over potassium carbonate, filtered and fractionated.There was obtained 27.6 g. (70%) of compound, 3.1. 98 C./0.3 n1rn., N1.5194.

A nulysis.-Calcd. for C H FN N, 2130%. N, 20.94%.

Found:

DIHYDROCHLORIDE SALT The dihydrochloride was prepared by adding etherealhydrochloric acid to a solution of the base in ethanol. The salt wasrecrystallized from methanol, Ml. 191192 C.

Analysis.Calcd. for C H Cl FN N, 15.55%; Cl,

26.25%. Found: N, 15.50%; Cl, 26.42%.

EXAMPLE 14- 1-(N-merizyl-N-benzylaminoethyl) -2-pa1m itoyl hydrazine Toa solution of 17.9 g. (0.1 mole) of N-rnethyl-N- benzylaminoethylhydrazine and 25.6 g. (0.1 mole) of palrnitic acid in 200 cc. of warmethanol was added a solution of 22.6 g. (0.11 mole) of dicyclohexylcarbodiimide in 75 cc. of ethanol. The solution was reiluxed for 12hours, refrigerated and 15 g. of dicyclohexyl urea were filtered off.After concentrating to half its volume, the solution was refluxedanother 12 hours resulting in the separation of a trace more ofmaterial. The solution was then taken to dryness and the 57.5 g. ofresidue were recrystallized from 400 cc. of boiling acetonitrile. Afterrefrigeration and filtration there was isolated 32.5 g. of thehydrazide, MP. -65 C. (unsharp).

DIHYDROCHLORI'DE S'ALT 30 g. of the hydrazide was dissolved in 1200 cc.of dry ether and filtered to remove some insoluble material. Afteraddition of ethereal hydrochloric acid there formed a gcl-likeprecipitate which hardened on refrigeration. After standing for 48 hoursin the refrigerator, the product was filtered and dried. Yield 24 g.(53%), shrinking at I ca. 85" C. and becoming translucent at ca. 115 C.

Analysis. Calcd. for C I-l Cl N O: N, 7.97%; Cl, 13.46%. Found: N,8.11%; Cl, 13.65%.

EXAMPLE 15 Z-(N-metlzyl-N- ,4-mcthylencdioa vbeuzyl)ominocthyl hydrazine3,4-CH O C1 N (CH C 11 N H-NH 'in vacuo, under nitrogen on a hot waterbath, until the residue was very turbid. The residue was taken up in 250mls. of water and, with cooling, made strongly alkaline with .1 OH. Ayellow oil separated and was decantedoff. The aqueous phase wasextracted three times with 150 cc. of ether. The oil and extracts werecombined and dried over anhydrous K C0 The ether was distilled off. The

other hour.

yield of crude residue was 38.4 g. It was fractionated in vacuo, undernitrogen, with a 3" column. Bl. 152157 C./0.6 mm. Yield 23.2 g. (47.3%),N 1.5487.

Analysis-Calm. for C I-1 N 0 N, 18.82%. Found: N, 17.42%.

DIHYDROCH'LORIDE SALT 19.8 g. (0.89 mole) of the base was dissolved in amixture of 300 cc. of anhydrous other and cc. of ethanol. With coolingand stirring it was acidified to pH 3.0 with ethereal HCl. The reactionwas very exothermic. A precipitate formed and mixture was chilled andthe yellow solid filtered off, washed and dried. Yield of crude yellowsolids 22.2 g., MP. 155 170 b. It was recrystallized in 800 cc. ofethanol and 150 cc. of methanol to yield 12.8 g. (48.1% MP. 189-191" C.

A5t6]j/SZS.CE11CC1. for C H NyJ Cl N, 14.19%; C]. 23.94%. Found: N,14.15%;Cl, 23.92%.

in a one liter "hree neck round bottom flask there was placed 53.7 g.(1.08 mole) of hydrazine hydrate and ml. of 1/ 1 methanol/ethanol. Themixture was heated to reflux with stirring and a solution of 42.8 g.(0.17 mole) or" 2-(N-rnethyl-N-o-methylbenzyl)-arninoethyl chloridehydrochloride in 200 mls. of 1/ 1 methanol/ ethanol added slowly in 2hours. When the addition was completed the mixture was refluxed for anhour. The solvents were distilled off in vacuo, under nitrogen on a hotwater bath until the residue was very turbid. The residue was taken upin 250 cc. of water and made strongly alkaline with K011. A yellow oilseparated and was decanted off. The aqueous phase was extracted threetimes with cc. of ether. 'The oil and extracts were combined and driedover anhydrous K CO The ether was distilled Off in vacuo, undernitrogen. The crude residue weighed 32.4 g. It was fractionated, invacuo,

under nitrogen, with a 5" column. BP. 93-94 C./ 0.15 min. Yield 17.0 g.(51.7%), N 1.5362.

[Tii1-5l!}/SZ S.C?tiCl. for (1 1 1 16 N, 21.74%. Found:

Drnr-Daocn-Loaron SALT 14.1 g. (0.07 mole) of the base was dissolved in25 cc. of ethanol and 280 cc. of anhydrous ether. With cooling andstirring it was acidified with ethereal HCl to pH 3.0. It was chilledand the white solids filtered 01f, washed and dried. Yield of crudesolids 18.6 g., MP. 162172 C. The product was recrystallized from aboiling mixture of 400 cc. of ethanol, 15s cc. of methanol, and 50 cc.of methyl nitrilc. The yield of cream colored solids was 8.9 g. (41.8%),MP. 182185 C. (uncorr.).

Ana sis.-Calcd. for C H JJ CI N, 15.79%; Cl, 26.64%. Found: N, 15.67%;Cl. 26.33%.

EXAMPLE 17 Z-(N -metlz y l-N-p-meihoxybenzyl -am inoeriz yl hydrazine p-C11 0 46C H NO 1IlNi1NH In a one liter three neclr round bottom flaskwas placed 74.2 g. (1.26 mole) of 85% hydrazine hydrate and 100 this. of1/ 1 methanol/ ethanol and the mixture then heated to reflux withstirring. There was then added dropwise to the refluxing solution, in 2hours, a solution of 52.2 (0.209 mole) of 2-(11hethyl-N-pmethoxyphenyl)- aminoethyl chloride hydrochloride in 200 ml.of 1/ 1 methanol/ethanol. Reliuxing was then continued for an- T'healcohol and excess hydrazine were distilled or? until the residue wasvery turbid. It was taken up in 300 mls. of water and made stronglyalkaline with KOH and extracted four times with 100 mls. of ether.

The combined extracts were dried over anhydrous K CQ and the etherdistilledofl. Crude residue 41.1 g. It was distilled through a 5" columnunder nitrogen. B.P. 140-145 C./1.2 mm. 1 Yield, 27.8 g. (66.4%), N

Analysis.Calcd. for C I-1 N 01 N, 13.38%. Found: N, 13.02%.

DIHYDROCHLORIDE SALT 2.1 g. (0.01 mole) of the base was dissolved in 20mls. of anhydrous ether and acidified with ethereal HCl to pH 3.0. Awhite precipitate formed. The mixture was chilled and then filtered, andthe precipitate washed with anhydrous ether and dried. The yield ofcrude white product was 2.7 g., M.P. 169-190 C. It was recrystallizedfrom 50 ml. of absolute ethanol and filtered and dried. Yield 1.7 g.(60.7%), M.P. 188-190 C.

Analysis.-Calcd. fOl' C11H21N3OC121 N, C1, 25.13%. Found: N, 5.00%; Cl,24.88%.

EXAMPLE 18 2-(N-methyl-N-m-methoxybenzyl)-amin0ethyl hydrazine m-CH OCHN(CH C H,NH-NH distilled off until very turbid and the residue was taken7 up in 300 ml. of water. It was made strongly alkaline with KOH andextracted four times with 200 ml. of ether.

The. combined extracts were dried over anhydrous K CO The ether wasdistilled off to give a crude residue, 55.2 g. It was distilled througha 5" column. B.P. 130- 136 C./0.65 mm. Yield, 33.0 g. (58.4%).

Analysis.-Calcd. for C H N O: N, 13.38%. Found: N, 12.14%.

DIHYDROCH'LORI-DE SALT A solution of 2.1 g. (0.01 mole) of the base in20 ml. of anhydrous ether was acidified, slowly with cooling andstirring, with ethereal HCl. A white gummy precipitate formed, 10 ml. ofabsolute ethanol was added and solids crystallized with cooling. Theprecipitate was filtered, washed and dried. The yield of crude yellowsolids was 2.5 g. (89.5%), M.P. 167-173 C. The product wasrecrystallized in 25 mls. of methanol. Yield,

1.58 g. (56%), M.P. 188-190 C. (uncorr.).

Analysis.Calcd. for C H N OCl N, 4.96%; Cl, 25.13%. Found: N, 5.04%; Cl,24.95%.

EXAMPLE 19 2- (N-methy l-N-m-ch lorobenzyl -wmin*ethyl hydrazine rn-Cl--CH N (CI-I C 'H NHNH N -f-(m chlorobenzyl) N methylaminoethyl chloride(0.26 mole) Was dissolved in 125 cc. of methanol and added to arefluxing solution of 84 g. (1.5 moles) of 85% hydrazine hydrate in 125cc. methanol. The addition took 6 hours. It was refluxed 10 hours afterthe addition. Upon cooling a precipitate of hydrazine hydrochloride cameout which was filtered. The filtrate was concentrated in vacuo and theresidue of two layers was picked up in 150 cc. of water. The mixturewasmade strongly alkaline with KOH and extracted three times with 100 cc.of ether. The ether extracts were combined and dried over anhydrous K COThe ether extract was concentrated on a steam bath and the residuedistilled under nitrogen through a column. Yield, 25.5 g. (0.12 mole),46% at 133-138 C./0.95-1.25 mm. N 1.5442.

1.2 Analysis.Calcd.for C H N3Cl: N, 13.10%; Cl, 16.62%. Found: N,12.44%; Cl, 16.85%.

.DIHYDROCHLORIDE SALT Twenty grams (0.09 mole) of N-(m-chlorobenzyD-N-'methylaminoethyl hydrazine was dissolved in 50 cc. of

EXAMl LE 20 p Z-(N-mezhyl-N-p-chlorobenzyl) -amin0ethyl hydrazine p-ClCHN (CH C H NH-NH In a one liter three neck round bottom flask was placed61.4 g. (1.04 moles) of hydrazine hydrate and mls. of 50/50ethanol/methanol. The mixture was heated to reflux with stirring. Asolution of 44.2 g. (0.17 mole) of2-(N-methyl-N-p-chlorophenyl)-aminoethyl chloride hydrochloride in rnls.of 50/50 ethanol/methanol was added dropwise to the refluxing solutionin 2.5 hours. Refluxing was continued for another hour. The alcohol andexcess hydrazine were distilled off until very turbid and the residuewas taken up in 150 mls. of water. It was made strongly alkaline withKOH and a yellow oil separated. The oil was decanted oil and the'aqueousphase extracted four timeswith 100 mls. of ether. The oil vand extracts(immiscible) were combined and dried over anhydrous K CO (The oil,became miscible with ether on drying.) The ether was distilled off togive a crude residue of 35.6 g. which was distilled through a 5 column.B.P. 116-119 C./0.35 mm. Yield, 25.0 g. (69%), N 1.5481.

Analysis.Calcd. for C H N Cl: N, 13.10%; Cl, 16.59%. Found: N,12.57%;Cl, 16.48%.

4 DIHYDROCHLOR-IDE SALT A solution of 2.6 g. (0.01 mole) of the base ina mixtureof 20 ml. of ether and 5 ml. of isopropanolwas acidifiedslowly, with cooling and stirring, with ethereal 'HCl. 7 A whiteprecipitate formed which was filtered,

washed and dried. The yield of crude solids was 2.9 g. (100%). M.P.14-9-160 C. The product was recrystallized in 25 mls. of methanol.Yield, 1.85 g. (64.5%), M.P. 18 3-l85 c. (uncorr.).

Analysis.-Calcd. for C10H18N3c1: N, 4.89% (l); ionic Cl, 24.74%; totalCl, 37.11%. Found: N, 5.01%; ionic 01, 24.73%; total (:1, 37.05%.

. EXAMPLE 21 2- (N -m ethy l-N -phenylamih0 -ethylhydrazirze I VN-0.H.NHNH,

In a one liter three neck round bottom flask there was placed 77.8 g.(1.32 moles) of 85% hydrazine hydrate and 150 ml. of absolute ethanol.This mixture was .heatedto reflux and there was added dropwise withstirring in 3 hours, a solution of 44 g. (0.26 mole) of 2-(N-methyl-N-phenyl)-aminoethyl chloride in 200 ml. of methanol. When theaddition was completed, the mixture was refluxed with stirring for 3hours. The alcohol was distilled off. To the residue was added 100 cc.of water and the mixture was made strongly alkaline with KOH. A greenoil separated and was decanted 01f. The aqueous phase was extractedthree, times with 100 cc. of ether. The oil and extracts were combinedand dried over anhydrous K CO The ether was distilled olI". The cruderesidue weighed 42.1 g. It was distilled 13 in vacuum under nitrogenwith a 5" column. The yield was 40.3 g. (97.9%), B.P. 105-109 C./0.2mm., N 1.5827.

Analysis.-Calcd. for C H N N, 25.43%. N, 24.70%.

Found:

EXAMPLE 22 2-(N-methyl-N-phenylamino) ethyl hydrazine maleate To asolution of 2.3 g. (0.02 mole) of maleic acid in 10 ml. of absoluteethanol there was added a solution of 3.3 g. (0.02 mole) of the base in5 ml. of absolute ethanol and 20 ml. of anhydrous ether. The reactionwas exothermic. The mixture was cooled. The white solids were filtered01f, washed with a 1/1 mixture of ethanol and anhydrous ether, anddried. The yield was 4.5 g. (80.4%), MP. 9091 C.

Analysis.-Calcd. for C I-1 N N, 14.94%; maleic acid, 41.26%. Found: N,15.08%; maleic acid, 42.55%.

EXAMPLE 23 2-(N-methyl-N-phenylamino)-ethylidenyl hydrazine Thiscompound is prepared by hydrolyzing N-methyl- N-phenylamino acetal andreacting with hydrazine hydrate as described in Example 2.

EXAMPLE 24 2-(N-methyl-N-phenylamino)ethyl hydrazine This compound isprepared by reducing the product of Example 24, i.e.,2-(N-methyl-N-phenylamino)ethylidenyl hydrazine, with LiAlH followingthe procedure of Example 4.

EXAMPLE 25 N-Z-(N'-0-chl0r0phenyl-N'-methyl-amino)-ethyl hydrazineFollowing the procedure of Example 6, this compound is prepared byhydrolyzing N-methyl-N-o-chlorobenzylamino .acetal, followed byreduction with LiAlI-I Various changes and modifications of theinvention can be made and, to the extent that such variationsincorporate the spirit of this invention, they are intended to beincluded within the scope of the appended claims.

What is claimed is:

1. A member of the group consisting of compounds of the formula andnontoxic acid addition salts thereof wherein A is a member of the groupconsisting of phenyl, lower alkylphenyl, halophenyl, loweralkoxy-phenyl, lower alkylenedioxyphenyl and pyridyl, R is a member ofthe group consisting of hydrogen and lower alhyl, R is a member of thegroup consisting of hydrogen and lower alkyl, Y is a lower alkylene ofnot more than 5 carbons, and B is lower alkylene.

2. A member of the group consisting of compounds of the formula andnontoxic acid addition salts thereof wherein A is a member of the groupconsisting of phenyl, lower alkylphenyl, halophenyl, loweralkoxy-ph-enyl, lower alkylenedioxyphenyl and pyridyl, R is a member ofthe group consisting of hydrogen and lower alkyl, R is a member of thegroup consisting of hydrogen and lower alkyl and B is lower alkylene.

3. A member of the group consisting of compounds of and nontoxic acidaddition salts thereof wherein A is a member of the group consisting ofphenyl, lower alkylphenyl, halophenyl, lower alkoxy-phenyl, loweralkylenedioxyphenyl and pyridyl, R is a member of the group consistingof hydrogen and lower alkyl, R is a member of the group consisting ofhydrogen and lower alkyl, Y is a lower alkylene of not more than 5carbons, and B is lower alkylene.

4. A member of the group consisting of compounds of the formula hydra-2-(N-methyl-N-methoxybenzyl)aminoethyl hydra- 2-(N-methyl-N-chlorobenzyl) -aminoethy1 hydra-N-(l-phenyl-Z-propyl)-aminoethyl hydrazine.2-(N-methyl-N-phenylamino)ethyl hydrazine.N-3-pyridyl-N-methylamino-Z-propyl hydrazine.2-(N-methyl-N-3',4-methylenedioxyphenyl)- aminoethyl hydrazine.

16. 2-(N-methyl-N-o-methylphenyl)-aminoethy1 hydrazine.

17. 2-(N-methylN-methoxyphenyl)-aminoethyl hydrazine.

10. 2-(N-methyl-N-chlorophenyl)-arninoethyl hydrazine.

References Cited by the Examiner UNITED STATES PATENTS 2,420,702 5/47Drewitt 260-569 2,695,297 11/54 Hellman et al. 260-296 2,792,403 5/57Blicke 260296 2,804,422 8/57 Schumann et a1. 16765 2,830,050 4/58 BielQ. 260--583 2,838,441 6/58 Allen et al. 16765 2,927,111 3/60 Biel260-293 2,930,795 3/60 Biel 260293 2,955,108 10/60 Omietanski 260'5833,051,707 8/62 Biel 260-583 OTHER REFERENCES Noller: Chem. of Org.Compds, 2nd ed., page 241 (1957).

Sidgewick: Org. Chem. of Nitrogen, page 28, (1927).

Sommer et al.: Chem. Abstracts, vol. 19, p. 3250 (1946).

WALTER A. MODANCE, Primary Examiner.

DUVAL T. MCCUTCHEN, Examiner.

1. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA 6.N-3-PYRIDYLMETHYL-N-METHYLAMINO-2-PROPYL HYDRAZINE.